Thiazole-substituted aminopyrimidines as spleen tyrosine kinase inhibitors

Abstract

The invention provides certain thiazole-substituted aminopyrimidine compounds of the Formula (I) (I), or pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R5, R6, and the subscripts r, s, and t are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds, and methods of using the compounds for treating diseases or conditions mediated by Spleen Tyrosine Kinase (Syk).

What is claimed is: 
     
       1. A compound of the Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  is selected from the group consisting of:
 (i) C 1 -C 3  alkyl; and 
 (ii) C 1 -C 3  fluoroalkyl; 
 
         R 2  is ring C B  , wherein ring C B  is selected from the group consisting of
 (a) a 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S; 
 (b) phenyl; and 
 (c) cyclohexenyl; 
 
         wherein ring C B  is unsubstituted or substituted with 1 to 3 R 7 , wherein each R 7  is independently C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo, —CN, —CH 2 —O—C 1 -C 3  alkyl, —S(O)—C 1 -C 3  alkyl, —S(O) 2 —C 1 -C 3  alkyl, amino, —N(H)—C 1 -C 3  alkyl, —N(C 1 -C 3  alkyl) 2 , —C(O)NH 2 , —C(O)N(H)-C 1 -C 3  alkyl, —C(O)N(C 1 -C 3  alkyl) 2 , or —C(O)N(H)-cyclopropyl; 
         R 3  is selected from the group of H and halo; 
         R 5  is —C(O)OR A  or —C(O)NH 2 ; 
         R 6  is C 1 -C 3  alkyl 
         the subscript r is 0, 1, or 2; 
         the subscript s is 0 or 1; 
         the subscript t is 0, 1, 2, 3, 4, or 5; 
         the subscript x is 0, 1, or 2; 
         R A  is independently selected from the group consisting of:
 (a) H; 
 (b) C 1 -C 8  alkyl; 
 (c) a group of the formula -M-R CH , wherein
 M is a bond or —(CH 2 ) n1 -, wherein the subscript n1 is 1 or 2; 
 R CH  is (a) aryl or C 3 -C 6  cycloalkyl optionally substituted with 1-3 groups independently selected from halo, C 1 -C 4  alkyl, or C 1 -C 4  alkoxy; or (b) a 5- to 6-membered monocyclic heterocycle containing 1 or 2 heteroatoms independently selected from the group consisting of N and O, wherein said heterocycle of R CH  is optionally substituted with 1 or 2 groups independently selected from the group consisting of oxo and C 1-3  alkyl; 
 
 (d) a group of the formula —(CH 2 ) n1 —R m  or —(CH 2 ) 2 —O—(CH 2 ) 2 —R m  wherein R m  is —CO 2 R m , —C(O)N(R m2 ) 2 , or —O(CO)R m1 ;
 R m1  is C 1 -C 4  alkyl; and 
 R m2  is H or C 1 -C 4  alkyl; 
 
 (e) a group of the formula —(CH 2 ) 2 —R n ,
 R n  is —OH, —O—(C 1 -C 4  alkyl), —O—(CH 2 ) 2 —O—(C 1 -C 4  alkyl), —NH 2 , —N(H)(C 1 -C 4  alkyl) or —N(C 1 -C 4  alkyl) 2 ; 
 
 (f) a group of the formula 
 
       
       
         
           
           
               
               
           
         
         
            wherein
 R o  is H or C 1 -C 4  alkyl; and 
 R p  is C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, or phenyl; and, 
 
           (g) a group of the formula 
         
       
       
         
           
           
               
               
           
         
         
            wherein R o  and R p  are as set forth above. 
         
       
     
     
       2. The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein ring C B  is pyrazolyl, tetrazolyl, thienyl, thiazolyl, phenyl, pyridyl, or cyclohexenyl; and
 wherein ring C B  is unsubstituted or substituted with 1 to 2 R 7  moieties. 
 
     
     
       3. The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein each R 7  is independently selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, amino, methoxy, methoxymethyl, —CN, —S(O) 2 CH 3 , and —C(O)N(H)-cyclopropyl. 
     
     
       4. The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein the subscript r is 0 or 2. 
     
     
       5. The compound of  claim 4  or a pharmaceutically acceptable salt thereof wherein the group 
       
         
           
           
               
               
           
         
       
     
     
       6. The compound of  claim 5  or a pharmaceutically acceptable salt thereof wherein R 5  is —CO 2 H, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , or —C(O)NH 2 . 
     
     
       7. The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 1  is —CF 3 . 
     
     
       8. The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein the compound of the Formula (I) has the Formula (IA) 
       
         
           
           
               
               
           
         
         wherein 
         R 2  is
 ring C B , wherein ring C B  is pyrazolyl, tetrazolyl, thienyl, thiazolyl, phenyl, pyridyl, or cyclohexenyl: 
 wherein ring C B  is unsubstituted or substituted with 1 to 2 R 7 , wherein each R 7  is independently selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, amino, methoxy, methoxymethyl, —CN, —S(O) 2 CH 3 , and —C(O)N(H)-cyclopropyl; 
 
         R 5  is —C(O)OR A  or —C(O)NH 2 ; and 
         R 6a  and R 6b  are independently H or methyl. 
       
     
     
       9. The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is —C(O)OR A . 
     
     
       10. The compound of  claim 9  or a pharmaceutically acceptable salt thereof, wherein R A  is H. 
     
     
       11. The compound of  claim 1  selected from the group consisting of:
 ethyl 4-(5-(3-(1H-pyrazol-4-yl)-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)-4-hydroxy-2-methylcyclohexanecarboxylate; 
 4-(5-(3-(1H-pyrazol-4-yl)-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)-4-hydroxy-2-methylcyclohexanecarboxylic acid; 
 4-(5-(3-(1H-pyrazol-4-yl)-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)-4-hydroxy-2-methylcyclohexanecarboxamide; 
 1-(5-(3-(1H-tetrazol-5-yl)-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)cyclobutanol; 
 4-hydroxy-2,2-dimethyl-4-(5-(3-(1-methyl-1H-pyrazol-4-yl)-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)cyclohexanecarboxylic acid; 
 4-{5-[3-(1-tert-butyl-1H-pyrazol-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-hydroxy-2,2-dimethyl-4-[5-(3-[1-(1-methylethyl)-1H-pyrazol-4-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid; 
 4-{5-[3-(1-ethyl-1H-pyrazol-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-hydroxy-2,2-dimethyl-4-[5-(3-pyridin-4-yl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid; 
 4-[5-(4′-fluoro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-hydroxy-4-{5-[3-(6-methoxypyridin-3-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-2,2-dimethylcyclohexanecarboxylic acid; 
 4-hydroxy-2,2-dimethyl-4-[5-(3-thiophen-3-yl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid; 
 4-{5-[3′-(cyclopropylcarbamoyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-hydroxy-2,2-dimethyl-4-{5-[3-(1H-pyrazol-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}cyclohexanecarboxylic acid; 
 4-hydroxy-2,2-dimethyl-4-{5-[3-(1H-pyrazol-3-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}cyclohexanecarboxylic acid; 
 4-[5-(3′-fluoro-4′-methoxy-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-hydroxy-4-{5-[4′-(methoxymethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl]-1,3-thiazol-2-yl}-2,2-dimethylcyclohexanecarboxylic acid; 
 4-[5-(2′,3′-difluoro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-{5-[3-(5-fluoropyridin-3-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-[5-(4′-fluoro-3′-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-hydroxy-2,2-dimethyl-4-{5-[2′-(methylsulfinyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl]-1,3-thiazol-2-yl}cyclohexanecarboxylic acid; 
 4-[5-(2′-chloro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-{5-[3-(6-aminopyridin-3-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-hydroxy-2,2-dimethyl-4-[5-(2′-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid; 
 4-[5-(3-cyclohex-1-en-1-yl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-[5-(2′-fluoro-5′-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-hydroxy-2,2-dimethyl-4-{5-[3-(3-methylthiophen-2-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}cyclohexanecarboxylic acid; 
 4-hydroxy-2,2-dimethyl-4-{5-[3-(4-methylthiophen-3-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}cyclohexanecarboxylic acid; 
 4-[5-(2′-fluoro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 4-hydroxy-2,2-dimethyl-4-(5-(3-(thiazol-2-yl)-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)cyclohexanecarboxylic acid; 
 4-hydroxy-2,2-dimethyl-4-[5-(3-thiophen-2-yl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid; and 
 4-[5-(4′-cyano-3′-fluoro-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
       12. The compound of  claim 8  or a pharmaceutically acceptable salt thereof, wherein R 5  is —C(O)OR A . 
     
     
       13. The compound of  claim 12 , or pharmaceutically acceptable salt thereof, wherein R A  is H. 
     
     
       14. A pharmaceutical composition comprising the compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceuticallly acceptable carrier.